Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells.

Drug repurposing Drug screening KRP203/Mocravimod Multi targets Multitarget drug One drug PI3K PI3P5K/Type III PIPK/PIKFYVE PI5P4K/Type II PIPK/ phosphatidylinositol 5-phosphate 4-kinase Phosphoinositide metabolism Polypharmacology

Journal

Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516

Informations de publication

Date de publication:
30 Oct 2023
Historique:
received: 06 08 2023
accepted: 22 08 2023
pmc-release: 30 10 2024
pubmed: 9 9 2023
medline: 9 9 2023
entrez: 8 9 2023
Statut: ppublish

Résumé

Increased phosphoinositide signaling is commonly associated with cancers. While "one-drug one-target" has been a major drug discovery strategy for cancer therapy, a "one-drug multi-targets" approach for phosphoinositide enzymes has the potential to offer a new therapeutic approach. In this study, we sought a new way to target phosphoinositides metabolism. Using a high-throughput phosphatidylinositol 5-phosphate 4-kinase-alpha (PI5P4Kα) assay, we have identified that the immunosuppressor KRP203/Mocravimod induces a significant perturbation in phosphoinositide metabolism in U87MG glioblastoma cells. Despite high sequence similarity of PI5P4K and PI4K isozymes, in vitro kinase assays showed that KRP203 activates some (e.g., PI5P4Kα, PI4KIIβ) while inhibiting other phosphoinositide kinases (e.g., PI5P4Kβ, γ, PI4KIIα, class I PI3K-p110α, δ, γ). Furthermore, KRP203 enhances PI3P5K/PIKFYVE's substrate selectivity for phosphatidylinositol (PI) while preserving its selectivity for PI(3)P. At cellular levels, 3 h of KRP203 treatment induces a prominent increase of PI(3)P and moderate increase of PI(5)P, PI(3,5)P

Identifiants

DOI: 10.1016/j.bbrc.2023.08.050 PMID: 37683456 PMC: PMC10559341
pubmed: 37683456
pii: S0006-291X(23)00996-8
doi: 10.1016/j.bbrc.2023.08.050
pmc: PMC10559341
mid: NIHMS1930435
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

116-121

Subventions

Organisme : NCI NIH HHS
ID : R01 CA255331
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM144426
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS089815
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Auteurs

Yoshiki Ikeda (Y)

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.

Mindy I Davis (MI)

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.

Kazutaka Sumita (K)

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Endovascular Surgery, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.

Yuxiang Zheng (Y)

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10007, USA.

Satoshi Kofuji (S)

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.

Mika Sasaki (M)

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.

Yoshihisa Hirota (Y)

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Minuma-ku, Saitama, 337-8570, Japan.

Rajan Pragani (R)

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.

Min Shen (M)

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.

Matthew B Boxer (MB)

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.

Koh Takeuchi (K)

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.

Toshiya Senda (T)

Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, 305-0801, Japan; Department of Accelerator Science, School of High Energy Accelerator Science, The Graduate University for Advanced Studies), Tsukuba, Ibaraki, 305-0801, Japan; Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.

Anton Simeonov (A)

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, 20850, USA.

Atsuo T Sasaki (AT)

Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0052, Japan; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, Cincinnati, OH, 45267, USA; Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, 734-8551, Japan. Electronic address: sasakiao@ucmail.uc.edu.

Classifications MeSH